Pharmacovigilance study of the association between dipeptidyl peptidase–4 inhibitors and angioedema using the FDA Adverse Event Reporting System (FAERS)

Dipeptidyl peptidase-4 (DPP-4) plays a minor role in degrading vasoactive peptides that cause angioedema when angiotensin-converting enzyme (ACE) is present and fully functional. This study investigated the association between DPP-4 inhibitors (DPP-4Is) and angioedema, including cases where the concomitant use of ACE inhibitors (ACEIs) was absent. We obtained data from the US Food and Drug Administration Adverse Event Reporting System and performed a disproportionality analysis, using the reporting odds ratio (ROR) and information component (IC) for signal detection in patients aged ≥ 40 years, stratified by age group and sex. No signal was detected for DPP-4Is when the entire dataset was analyzed. However, a signal was detected for the entire female subset group, the three stratified female groups aged ≥ 60 years, and males in their 40 s. After excluding the data of concomitant ACEI users, most ROR and IC values were lower and significant only for females in their 60 s and males aged ≥ 80 years. Regarding individual DPP-4Is signals, those detected for saxagliptin and sitagliptin in some age groups disappeared after excluding the data of ACEI users. Notably, linagliptin was the only DPP-4I where signals were detected in most female groups, regardless of age and without concomitant ACEI use. Our findings suggest that some DPP-4Is were associated with a higher reporting of angioedema as per age and sex, even in the absence of concomitant ACEI use.

Analysis in subset data stratified by age and sex for patients without concomitant ACEI treatment. Overall, 229,376 of the 3,701,618 (6.2%) records of patients using DPP-4Is showed that they received concomitant treatment with ACEIs. The remaining 3,472,242 patients usedDPP-4Is alone; of these 72,369 had adverse event reports related to angioedema. Our analysis of the association between DPP-4I and angioedema revealed that most ROR and IC values (95% CI) were less than those obtained when the whole dataset was analyzed ( Fig. 2 and Table 3). In the analysis for all DPP-4Is, a significant association was found only for females in their 60 s  (Table 3).

Discussion
Vasoactive peptide-induced angioedema may occur not only in ACEIs but also in DPP-4Is. This study evaluated the association between DPP-4Is and angioedema, including cases with and without the concomitant use of ACEIs. When we stratified the data according to age group and sex, we detected a signal for the female subset, three female age groups with patients aged ≥ 60 s, and the group of males in their 40 s. ON excluding ACEI users from the whole dataset, we only detected a signal for females in their 60 s and males aged ≥ 80 years. Individually,   From the stratified analysis in our study, the number of detected signals for DPP-4I-associated angioedema was more in the female groups than in the male groups (Fig. 1, Table 2) and more in the elderly groups than in the middle-adulthood groups (Fig. 1, Table 2). Generally, the incidence of drug-induced angioedema has been reported as higher in females 25,26 , and older age has been associated with a higher incidence of angioedema 27 , which supports our results.
A previous study using pharmacovigilance databases also reported the association between DPP-4I and angioedema 28,29 . Lepelley et al. evaluated the association of an increased angioedema reporting risk using the World Health Organization's pharmacovigilance database, reporting that exposure to DPP-4I alone was not associated with a disproportionality signal for angioedema 28 . Moreover, in another study using the Japanese Adverse Drug Event Report database, the authors also performed a disproportionality analysis to evaluate DPP-4I/ACEIinduced angioedema and concluded that DPP-4I tended to have different effects on the onset of angioedema from ACEI in clinical practice, because an inverse association of DPP-4I with angioedema was found. The difference in the conclusion could be attributed to the use of different pharmacovigilance databases, which include information on different races. Additionally, although the adverse event (angioedema) was defined according to MedDRA in both cases, there was a slight difference in the selection of PTs. Moreover, our study classified the data in more detail by stratification according to age and sex.
Some case reports have suggested that linagliptin can cause acute renal failure with hypotension and hyperkalemia when added to the treatment regimens of patients already receiving ACEIs 30,31 . Moreover, a recent in silico and in vivo study reported that many DPP-4Is, including linagliptin, could potentially inhibit ACE in concentrations close to those required for DPP-4 inhibition 32 . These results suggest that linagliptin can inhibit two enzymes, both of which contribute to BK and SP degradation, and it may be reasonable to assume that linagliptin causes angioedema.
Conversely, it was also reported that sitagliptin inhibits both DPP-4 and ACE 32 , despite the detection of a limited signal for sitagliptin in our study (Tables 2 and 3). A possible explanation may be the different pharmacokinetics of these drugs. In other words, since the more complete or sustained ACE inhibition seen with the longer-acting agents may be detrimental 33 , DPP-4Is are suggested to inhibit ACEs for a longer-acting duration and also be more likely to cause angioedema than shorter-acting agents. The half-life of linagliptin and sitagliptin is 104-113 h 34 and 9-14 h 35 , respectively. Further studies are necessary to determine whether such inhibitory effects occur in clinical settings.
It has been proposed that patients with a history of ACEI-induced angioedema are at risk for recurrent angioedema with DPP-4Is 36 . This may be explained by reports that the enzymatic activity of DPP-4 is innately reduced in the sera of such patients compared with the sera of ACEI-treated patients without angioedema [37][38][39] . Furthermore, the concentrations of enzymes involved in BK and SP degradation were reported to have drastically reduced compared with the reference range for at least a year after inhibition by DPP-4Is and ACEIs 37,40 . Therefore, the recurrence of angioedema in patients with such a history warrants additional care, given the possible inhibition of BK and SP degradation, even without DPP-4Is and ACEIs administration.
This study suggests that the use of DPP-4Is, even in the absence of concomitant ACEI use, is associated with angioedema in clinical practice. To determine whether this is a class effect of DPP-4I, further studies are essential.
In any case, clinicians should be aware of the possible association as seen in this study.
Although the analysis of a spontaneous report is a valuable method for identifying signals, there are potential limitations of such databases that may have affected the interpretation of our findings. First, adverse events are not always induced by medication. Second, angioedema is influenced by many confounding factors, such as comorbidities including chronic heart failure or coronary artery disease 4,5 ; the concomitant administration of drugs other than ACEIs, such as angiotensin receptor blockers, antibiotics, and nonsteroidal anti-inflammatory drugs 41 ; and smoking 5,6 , which we did not take into consideration in this study. Although the incidence of angioedema has been reported to be lower in patients with diabetes mellitus 4, 6 , we had to include such patients because DPP-4Is are used to treat diabetes mellitus in clinical practice. Third, as mentioned above, duplicate reports for the same case could be included in spontaneous reporting systems, and, conversely, underreporting may occur. Fourth, data are missing and drug names are frequently misspelled in the FAERS database. Additionally, concerning data mining techniques, given that control populations are not included in spontaneous Table 2. Association between DPP-4 inhibitors and angioedema by stratified age and sex with whole data set. DPP-4 dipeptidyl peptidase-4, ROR reporting odds ratio, IC information component, CI confidence interval. a Signal was detected.